The skin provides a barrier that protects the host from environmental pathogens. A break in this barrier increases susceptibility to life-threatening infection. When invasive microorganisms gain entry to the host, circulating immune cells and local epithelial cells use Toll-like receptors (TLR) to recognize ‘pathogen associated molecular patterns’ (PAMPs), and thereby initiate a protective response (Kawai et al., Immunity 2011; 34: 637-50). Recent studies show that stimulating the innate immune system serves an additional function: it accelerates wound repair. Specifically, TLR4 ligands and TLR9 ligands promote healing by inducing the production of cytokines, chemokines, and growth factors that act on inflammatory and epithelial cells at the wound site (see, for example, Sato et al., Wound Repair Regen 2010; 18: 586-93; Koff et al., J Immunol 2006; 177: 8693-700; Yamamoto et al., Biomaterials 2011; 32: 4238-42).
Wound repair is a dynamic process that involves a complex interaction between resident and infiltrating cells, extracellular matrix molecules, and soluble factors. Tissue healing proceeds in three overlapping phases: inflammation, tissue formation, and tissue remodeling (Singer and Clarke, N Engl. J. Med 1999; 341: 738-46). These events are influenced by cytokines and chemokines, including IL-1β and CCL2, that are produced during the inflammatory phase and speed wound healing (Barrients et al., Wound Repair Regen 2008; 16: 585-601; Eming et al., J Invest Dermatol 2007; 127: 514-25). IL-1β is produced by neutrophils, monocytes and macrophages, and functions to increase keratinocyte migration/proliferation and activate fibroblasts (Raja et al., Front Biosci 2007; 12: 2849-68; Kormine et al., J Biol Chem 2000; 275: 32077-88). Inhibition of IL-1 signaling decreases the production of IL-6 and TNFa, suggesting that IL-1 plays a pivotal role during the inflammatory phase of wound healing (Hu et al., Anesth Analg 2010; 111: 1525-33). The chemokine CCL2 is also an active participant in the wound healing process (Barrientos et al., Wound Repair Regen 2008; 16: 585-601). CCL2 influences both the recruitment of inflammatory cells and the production of other factors that support wound healing (Raja et al., supra; Christopherson and Hromas, Stem Cells 2001; 19: 388-96). In this context, wound healing is significantly delayed in CCL2 KO mice, as manifested by delayed re-epithelialization, angiogenesis and collagen synthesis (Low et al., Am J Pathol 2001; 159: 457-63). Interferon (IFN) a and IFNb levels also increase at wound sites, where they promote epidermal regeneration and wound repair (Gregoria et al. J Exp Med 2010; 207: 2921-30; Lin et al., J Immunol 2011; 186: 3710-7).
Efforts to reduce wound infection generally rely on local antibiotic treatment to eliminate contaminating bacteria. However, since bacterial PAMPS stimulate an innate immune response that accelerates wound repair, sterilizing the wound might reduce PAMP concentrations and thus indirectly slow healing. A need remains for agents that can increase wound healing in the presence of antibiotics.